Clinical tester wash and method

ABSTRACT

A clinical tester has been described that includes a probe to aspirate a fluid. The probe is washed between aspirations to reduce carryover. The wash operation includes both an internal and an external wash, where the internal wash operation is terminated prior to terminating the external wash. In one embodiment, the probe wash can be implemented on an integrated clinical chemistry/immunoassay tester.

This application is a divisional application claiming priority from U.S.application Ser. No. 10/158,495, filed May 29, 2002.

FIELD OF THE INVENTION

The present invention relates generally to clinical test equipment andin particular the present invention relates to reduction of samplecarryover in clinical test equipment.

BACKGROUND OF THE INVENTION

Although various known clinical analyzers for chemical, immunochemicaland biological testing of samples are available, clinical technology israpidly changing due to increasing demands in the clinical laboratory toprovide new levels of service. These new levels of service must be morecost effective to decrease the operating expenditures such as labor costand the like, and must provide shorter turnaround time of test results.Modernization of analytical apparatus and procedure demandsconsolidation of workstations to meet the growing challenge placed onclinical laboratories.

Generally, analysis of a test sample involves the reaction of testsamples with one or more reagents with respect to one or more analyteswherein it is frequently desired that the analysis be performed on aselective basis with respect to each test sample. Automated clinicalanalysis systems analyze a test sample for one or more characteristics.Automated clinical analyzers also provide results much more rapidlywhile frequently avoiding operator or technician error, thus placingemphasis on accuracy and repeatability of a variety of tests. Automatedclinical analyzers presently available for routine laboratory testsinclude a transport or conveyor system designed to transport containersof sample liquids between various operating stations.

Some of the presently available automated clinical analyzers, such asautomated immunoassay analyzers, utilize procedures involving a varietyof different assay steps. A robotic arm automatically processes the testsamples with a probe and a carousel, or robotic track, that positionsthe samples for processing. A typical tester has a sample probe arm tosample fluids and deposit the samples in a reaction vessel. One or morereagents are added to the vessel using reagent probe arms. The sampleand reagent probe arms include a probe that can be moved between sampleor reagent locations, the reagent vessel and wash stations.

Clinical chemistry and immunoassay testers have traditionally beenstandalone systems. These systems can be combined using a commontransport system to provide a more efficient integrated system. Previousstandalone chemistry analyzers did not require sample-to-samplecarryover performance requirements of an integrated clinical chemistryand immunoassay system. As laboratories integrate automated analyticalsystems, between-sample carryover becomes a critical goal. Manycompanies have elected to overcome this problem through use ofdisposable probe tips, but this approach is costly, wasteful and lessreliable. Another safeguard is to prioritize test sequencing such thatimmunoassay sampling is done prior to all chemistry tests. This approachimpacts chemistry turnaround time and lowers total workflow throughput.Yet another method to reduce sample carryover is to flush the systemwith large amounts of fluids (buffer, water, detergents).

For the reasons stated above, and for other reasons stated below whichwill become apparent to those skilled in the art upon reading andunderstanding the present specification, there is a need in the art fora reduction in sample carryover in clinical test equipment.

SUMMARY OF THE INVENTION

The above-mentioned problems with sample carryover and other problemsare addressed by the present invention and will be understood by readingand studying the following specification.

In one embodiment, a fluid tester comprises a probe having an interiorregion and an exterior surface. The probe is used to selectivelyaspirate a fluid into the interior region. A first wash mechanism iscoupled to the probe to dispense a wash fluid through the interiorregion of the probe for a first predetermined period. A second washmechanism is located to dispense the wash fluid on the exterior surfaceof the probe for a second predetermined period. The second predeterminedperiod extends beyond the first predetermined period.

In another embodiment, a method of cleaning a probe comprises flushingan interior region of the probe with a wash fluid for X seconds, andsimultaneously flushing an exterior surface of the probe with the washfluid for Y seconds, wherein Y is greater than X.

A method of sample carryover in an integrated chemistry and immunoassayanalyzer comprises aspirating a first test sample from a first samplecontainer using a probe, depositing the first test sample into areaction vessel and performing a chemical analysis of the test sample.The probe is washed by pumping a wash fluid through an interior regionof the probe and pumping the wash fluid on the exterior of the probe.The pumping of the wash fluid is terminated from the interior regionprior to terminating the pumping of the exterior. A second test sampleis then aspirated from a second sample container using the probe.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of a clinical tester of an embodiment ofthe present invention;

FIG. 1B is a clinical chemistry analyzer of the tester of FIG. 1A;

FIG. 1C is an immunoassay analyzer of the tester of FIG. 1A;

FIG. 2 illustrates a probe arm of the clinical tester of FIG. 1; and

FIG. 3 is a simplified cross-section of a probe in a wash station.

DETAILED DESCRIPTION OF THE DRAWINGS

In the following detailed description of the preferred embodiments,reference is made to the accompanying drawings, which form a parthereof, and in which is shown by way of illustration specific preferredembodiments in which the inventions may be practiced. These embodimentsare described in sufficient detail to enable those skilled in the art topractice the invention, and it is to be understood that otherembodiments may be utilized and that logical, mechanical and electricalchanges may be made without departing from the spirit and scope of thepresent invention. The following detailed description is, therefore, notto be taken in a limiting sense, and the scope of the present inventionis defined only by the claims.

The term “test sample”, as used herein, refers to a test material thatcan be used directly as obtained from a source or following apretreatment to modify the character of the sample. The test sample canbe derived from any biological source, such as physiological fluid,including, whole blood, serum, plasma, saliva, ocular lens fluid,cerebral spinal fluid, sweat, urine, milk, ascites fluid, raucous,synovial fluid, peritoneal fluid, amniotic fluid or the like.

The term “carryover” refers to cross-contamination or contact transferbetween test samples. Carryover is a byproduct of using a common sampleprobe for multiple test samples.

Between-sample carryover is a critical factor to ensure result integrityon automated analytical systems. Immunoassay analyzers traditionallymeet a sample-to-sample carryover goal of less than 0.1 ppm. Clinicalchemistry systems utilize methodologies that are less sensitive andrarely characterized using carryover requirements to this level. Aslaboratories consolidate analytical systems, however, the between-samplecarryover demands for immunoassay analyzers become applicable toclinical chemistry systems as well. Achieving a between-sample carryovergoal of less than 0.1 ppm for an integrated immunoassay and clinicalchemistry system can impact marketability of other variables includingspecimen throughput, system consumables, test prioritization, and samplepre-aliquoting.

Extensive research on an integrated system of an embodiment of thepresent invention identified critical variables associated withsample-to-sample carryover. High-speed video was used for qualitativecharacterization of the sample probe wash while concentrated samples ofhepatitis surface-antigen (HbsAg) were used to quantitatively assesscarryover performance. A probe wash protocol of an embodiment of theinvention passes the between-sample carryover limit of 0.1 ppm withoutsample pre-aliquoting, use of additional consumables, testprioritization, or significant impact to system specimen throughput.Critical variables include clinical chemistry sampling/aspirationvolumes and external sample probe wash duration, sequencing relative tothe internal sample probe wash. Other variables include positioning ofthe sample probe within the sample wash cup, sample wash cup design andexternal sample wash flow volumes/rates.

An embodiment of a wash protocol dictates the between sample washmechanism based on clinical chemistry sampling volume. The wash includesan external wash and an internal wash of the sample probe. All specimenswith a maximum chemistry sampling volume below a predetermined threshold(such as 15 μL or less) are effectively washed using an extended singlecycle wash mechanism. It is noted that a ‘dummy’ fluid volume may beaspirated in addition to the fluid sample volume. The dummy volumeprovides a buffer between the sample fluid and residual fluid in theprobe. The dummy volume is not included in the sample volume levelsdescribed herein. The extended single cycle wash mechanism utilizes aone second external probe wash that ends 100 ms after the internal probewash. This timing relationship between the internal and external washsequencing is particularly crucial for acceptable carryover performance.Specimens that are processed with chemistry sampling volumes exceedingthe threshold (15.1 μL or more) are washed using the same extendedsingle cycle wash mechanism but also undergo an additional 3.2 secondsof supplemental external wash. The wash protocol of the presentinvention, as explained below, is not limited to a specific timingduration or over-lap time between the termination of internal andexternal washes.

Between-Sample Carryover was quantitatively evaluated using recombinantsamples of concentrated hepatitis surface-antigen (HbsAg) in a pooledhuman serum matrix. Each concentrated HBsAg sample (with approximateimmuno-reactivity of 4 mg/mL) was followed by pooled normal human serum(pre-screened non-reactive for HbsAg) and processed on a chemistryanalyzer. The pooled human serum samples were evaluated on animmunoassay analyzer for HbsAg activity. Results were compared againstserial dilutions of the concentrated stock. If the pooled human serumresults exceeded that of the 0.1 ppm dilution of the concentrated stock,a test run was considered a failure. The magnitude of the failure wascalculated by converting the reported concentration of the serumdiluents into units of ppm from the reference dilution. Test conditionswere created to represent worst-case performance and test resultconfidence. The clinical chemistry sample volume was defined at 35 μL, atypical maximum sample volume for a chemistry application. HbsAg sampleswere processed in duplicate to ensure result integrity.

Results demonstrated a sample carryover performance trend associatedwith sample probe aspiration volume. As the clinical chemistry samplevolume increases, between-sample carryover failures also increase. Mostsystems fail between-sample carryover with a frequency higher than 50%(without optimization critical parameters) at the maximum clinicalchemistry sampling volume of 35 μL. The relationship between samplevolume and sample-to-sample carryover performance is significant tounderstanding the mode of failure. This is because trending demonstratesthat internal contamination of the sample probe has an impact onsample-to-sample carryover. The sample probe aspirates a test samplefrom a sample tube and immediately dispenses the sample volume into areaction vessel prior to entrance into a wash station. Anover-aspiration or dummy volume is dispensed at the wash station butthis volume is consistent and independent of chemistry sample volume(under the protocol test conditions). Since the frequency of thecarryover increases with chemistry sample volume and since this samplevolume is dispensed prior to external wash of the probe, it wastheorized that the source of the carryover (leading to thebetween-sample failures) resulted from internal contamination of thesample probe. This theory was supported by a supplemental investigationthat demonstrated that carryover failures were still prevalent withoutany dummy/over aspiration being dispensed at the sample wash station.Residual carryover remained on the external surface of the sample probefollowing sample probe washing, even when the probe did not dispense anyconcentrated sample at the wash station. The frequency of samplecarryover failures can be reduced using supplemental probe washes.Unfortunately, supplemental washes require additional instrument cyclesthat can degrade system specimen throughput.

A second variable to carryover performance is wash sequencing at thesample wash station. Further analysis of wash conditions at the samplewash station lead to a study evaluating external wash sequencingrelative to the internal wash. Success of the probe wash was lessdependent on the external wash duration than it was on the stopsequencing of the external wash relative to the internal wash. If theinternal wash stops after the external wash, carryover performance issignificantly worse than if the external wash if ends after the internalwash. This relationship supports a theory that internal contamination ofthe probe is a source for the external between-sample carryover. Onewash protocol utilizes a one second external probe wash that extendsbeyond the stop time of the internal wash to improve carryoverperformance at low sample volumes. A supplemental washing that wouldhave required an additional instrument cycle is not required to meetcarryover performance criteria.

Further studies demonstrated additional variables associated withbetween-sample carryover performance. These include wash cup design,hardware alignment at the sample wash station, and wash flowrates/volume. These variables are significant and require optimizationfor carryover performance. Failure to optimize these parameters cancause carryover failures. However, optimization, of these parameterswill not create a passing condition without control of the criticalvariables of chemistry sampling volume and wash sequencing.

Referring to FIG. 1A, a perspective view of a simplified integratedclinical test system 100 of an embodiment of the present invention. Thetest system includes a clinical chemistry tester 102 and an immunoassaytester 104, see FIGS. 1B and 1C for more detail. The two testers share acommon sample transporter 106 that allows linear movement of test sampletubes 108 between the two testers.

Each tester has a sample probe arm 110/112 that includes a probe 114(see FIG. 2). The arms can move in both a horizontal arc and verticaldirections. The probe aspirates a test sample from tube 108 located onthe transporter 106. The probe arm then moves to a sample vessel (notshown) and deposits the aspirated sample. After the sample has beendischarged from the probe, the arm moves to a wash station 120 where theprobe is washed. The sample vessel is moved to a location where areagent is added to the sample by a reagent arm 122. The reagent arm ismovable between a reagent location, the sample vessel and the washstation. The sample vessel may receive additional reagents and is thensubjected to chemistry testing, as know to those skilled in the art. Asecond reagent arm 123 can be included to provide a second reagent tothe sample vessel.

The sample tube 108 located on the transporter 106 is then moved to alocation near the immunoassay tester 104, FIG. 1C. The immunoassaytester is similar in operation to the clinical chemistry tester in thata test sample from the sample tube is aspirated using sample probe 114of sample probe arm 112. The sample arm then moves to a sample vessel(not shown) and deposits the aspirated sample. After the sample has beendischarged from the probe, the arm moves to a wash station (not shown)where the probe is washed. The sample vessel is moved to a locationwhere a reagent is added to the sample by a reagent probe arm 115. Thereagent arm is movable between a reagent location, the sample vessel andthe wash station. The sample vessel may receive additional reagents andis then subjected to testing, as know to those skilled in the art. It isclear that sample carryover, or contamination, can occur if the sampleprobes are not cleaned between aspirations of different test samples.

FIG. 2 illustrates an example probe arm 110. The arm includes a probe114 that can be moved about a horizontal arc and in a verticaldirection. The probe has a hollow center that allows aspiration of afluid and the subsequent introduction of a wash fluid. The mechanics ofthe probe arm are not described in detail herein, but are generally knowto those skilled in the art. For purposes of understanding theinvention, the arm is controllable to regulate the amount of sampleaspirated and the amount and duration of wash fluid that flows throughthe probe.

Referring to FIG. 3, a cross-section view of a probe 114 and wash cup126 are illustrated. The size and shape of the probe and wash cup areillustrative only and not intended to reflect actual designs or sizes.Those skilled in the art with the benefit of the present descriptionwill appreciate that the probe and wash cup design can vary withoutdeparting from the present invention. The probe is substantiallytube-shaped and includes an exterior surface 132 and an interior surface130. An interior wash dispenser 136, or nozzle, is located to dischargea wash fluid into the interior region of the probe. During a washoperation, the probe is vertically positioned in the wash cup. The washcup includes one or more exterior wash dispensers 138, or nozzles,positioned to spray a wash fluid toward a center region of the cup andonto the exterior of the probe.

The wash fluid pumped through the probe and on its exterior is the samefluid and depends upon the material that is to be removed from theprobe. The wash fluid can be located in a common reservoir 140 andpumped to the nozzles using separate pumps 142 and 144. Alternately, asingle pump and controllable valves can be used to pump the wash fluidto the nozzles. The present invention is not limited to a specific pumpdesign, provided the termination of the internal fluid and the externalfluid can be separately controlled by pump(s) controller 150. The term‘pump’ is intended to include any mechanism that allows for controlledmovement of a liquid, such as the wash fluid.

As explained above, the probe needs to be sufficiently cleaned betweensample aspirations to reduce sample carryover. The sample carryover canbe a test sample or reagent depending upon the probe. The internal washis terminated prior to terminating the external wash. This terminationoverlap significantly reduces sample carryover and allows clinicalchemistry testers to meet restrictive specifications of immunoassaytesters. One example wash for chemistry sampling volume below apredetermined threshold (such as 15 μL or less) includes a one secondexternal sample probe wash that ends 100 ms after the internal sampleprobe wash. The external wash can begin prior to the internal washwithout departing from the present invention.

The present invention is not limited to an integrated clinicalchemistry/immunoassay tester, and other analytical systems can utilizethe relationship of between-sample carryover performance to improvesample wash parameters. This includes other clinical chemistry andimmunoassay systems as well as hematology and other methodologies. Thewash method can also be used utilized for reagent carryover washing,sample pretreatment instrumentation, and with laboratory automationsystems.

CONCLUSION

A clinical tester has been described that includes a probe to aspirate afluid. The probe is washed between aspirations to reduce carryover. Thewash operation includes both an internal and an external wash, where theinternal wash operation is terminated prior to terminating the externalwash. In one embodiment, the probe wash can be implemented on anintegrated clinical chemistry/immunoassay tester.

Although specific embodiments have been illustrated and describedherein, it will be appreciated by those of ordinary skill in the artthat any arrangement, which is calculated to achieve the same purpose,may be substituted for the specific embodiment shown. This applicationis intended to cover any adaptations or variations of the presentinvention. Therefore, it is manifestly intended that this invention belimited only by the claims and the equivalents thereof.

1. A method of cleaning a fluid probe comprising: flushing an interiorregion of the fluid probe with a wash fluid for X seconds; andsimultaneously flushing an exterior surface of the fluid probe with thewash fluid for Y seconds, wherein Y is greater than X.
 2. The method ofclaim 1 where a difference between a termination time of the interiorregion flush and a termination time of the exterior surface flush isabout 0.1 Y.
 3. The method of claim 2 where Y is approximately onesecond.
 4. A method of reducing sample carryover in an integratedchemistry and immunoassay analyzer comprising: aspirating a first testsample from a first sample container using a probe; depositing the firsttest sample into a reaction vessel; performing a clinical analysis ofthe test sample; washing the probe by pumping a wash fluid through aninterior region of the probe and pumping the wash fluid on an exteriorof the probe, wherein the pumping of the wash fluid is terminated fromthe interior region prior to terminating the pumping of the exterior;and aspirating a second test sample from a second sample container usingthe probe.
 5. The method of claim 4 wherein the pumping of the washfluid on the exterior starts prior to pumping the wash fluid through theinterior region.
 6. The method of claim 5 wherein the wash fluid ispumped on the exterior for about one second.
 7. The method of claim 6wherein the pumping of the wash fluid through the interior region isterminated about 0.1 seconds prior to terminating the pumping of thewash fluid on the exterior.
 8. The method of claim 4 further comprising:aspirating a second test sample from the first sample container using asecond probe; depositing the second test sample into a second reactionvessel; and performing an immunoassay analysis of the second testsample.
 9. The method of claim 8 wherein the clinical analysis is eithera chemistry or immunoassay analysis.
 10. A method of cleaning a probecomprising: activating a first pump to pump a wash fluid through aninterior region of the probe; activating a second pump to pump the washfluid onto an exterior region of the probe; deactivating the first pumpafter a first predetermined time period; and deactivating the secondpump after a second predetermined time period, wherein the secondpredetermined time period is longer than the first predetermined timeperiod.
 11. A method of washing a probe comprising: determining anamount of fluid to be aspirated inside the probe; and selecting anexternal wash profile in response to the amount of fluid aspiratedinside the probe.
 12. The method of claim 11 wherein the wash profilecomprises a first wash sequence having both an internal and externalprobe wash, and an extended external wash if the amount of fluidaspirated exceeds a predetermined threshold.
 13. The method of claim 12wherein the extended external wash is about three times as long as thefirst wash sequence.
 14. A method of reducing carryover in a clinicaltester as a result of external probe contamination comprising: insertingthe probe into a fluid; determining an amount of fluid to be aspiratedinside the probe; dispensing the aspirated fluid; washing the inside ofthe probe; and selecting an external wash profile in response to theamount of fluid aspirated inside the fluid probe, wherein an extendedexternal wash is provided if the amount of fluid aspirated exceeds apre-determined amount.